Retinal degeneration is triggered by mutations in a large number of photoreceptor-expressed genes. Given the diversity of biochemical roles of these genes, each mutant must have distinct primary effects on photoreceptor cell biology. It is remarkable that the diversity of genetic insults result in retinal degeneration via similar morphological landmarks, suggesting the possibility of shared cell death events. During the previous granting cycle, an unbiased approach was successfully employed to identify genes that act in these retinal degeneration processes. Among experimental animals used in vision research, this type of approach is feasible only in Drosophila. Significantly, the approach has implicated non-caspase dependent pathways of cell death as the critical component in the progression of retinal disease. The three aims of this proposal focus on the analysis of identified molecular components of these pathways. Their role in the degeneration process will be studied by a combination of genetic, cell biological and molecular approaches. The effort is expected to provide new information on the cellular mechanisms controlling retinal degeneration. Thus, the proposal addresses one of the major goals of the National Plan released by the National Eye Institute in 2004. This five year plan includes, in the category of retinal disease, to "identify the genes involved in both inherited and retinal degenerative diseases and determine the pathophysiological mechanisms underlying the disease progression triggered by these mutations".